5-nitro-2,2&#39;-thiobisthiazole compounds

ABSTRACT

1. 5-NITRO-2,2&#39;&#39;-THIOBISTHIAZOLE COMPOUNDS THAT ARE REPRESENTED BY THE FORMULA   2-(R1-S-),5-(O2N-)THIAZOLE   WHERE R1 REPRESENTS A MEMBER OF THE CLASS CONSISTING OF 2-THIAZOLYL, 4-METHYL-2-THIAZOLYL, 4-ETHYL-2-THIAZOLYL, 4,5DIMETHYL-2-THIAZOLYL, AND 4,5,6,7-TETRAHYDRO-2-BENZOTHIAZOLYL.

UnitedStates Patent 3,839,348 -NITRO-2,2'-THIOBISTHIAZOLE COMPOUNDSEdward F. Elslager and Donald F. Worth, Ann Arbor,

Mich., assignors t0 Parke, Davis & Company, Detroit, Mich. No Drawing.Filed Feb. 20, 1973, Ser. No. 333,624 Int. Cl. C07d 91/38 US. Cl. 260302F 6 Claims ABSTRACT OF THE DISCLOSURE S-nitro-2,2'-thiobisthiazolecompounds represented by the formula N OgNl JS-R where R represents2-thiazolyl, 4-methy1-2-thiazolyl, 4- ethyl-2-thiazolyl,4,S-dimethyl-l-thiazolyl, or 4,5,6,7-tetrahydro-Z-benzothiazolyl; andtheir production by reacting 2-bromo-S-nitrothiazol with an appropriatethiazolyl mercaptan compound or an alkali metal salt thereof. Thecompounds are useful as chemotherapeutic agents having antifungal andantibacterial activity.

SUMMARY AND DETAILED DESCRIPTION The present invention relates to newthiazole compounds that are useful as chemotherapeutic agents and tomethods for their production. More particularly, the invention relatesto new 5-nitr0-1,2-thiobisthiazole compounds that are represented by theformula where R represents 2-thiazolyl, 4-methyl-2-thiazolyl, 4-ethyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, or4,5,6,7-tetrahydro-2-benzothiazolyl.

In accord with the invention, compounds having formula I above areproduced by reacting 2-bromo-5-nitrothiazole, which has the formula,

with a mercaptan compound having the formula R --SH III or an alkalimetal salt thereof, where R has the same meaning as given above. Thereaction is best carried out in a non-reactive solvent medium. Suitablesolvents include lower alkanols and lower aliphatic ketones. Preferredsolvents are methanol and acetone. When it is desired to use an alkalimetal salt of the mercaptan com- .pound of formula III as one of thereactants, the salt is formed by adding a base, such as an alkali metalalkoxide, to the reaction mixture. Sodium methoxide is a preferred basefor this purpose. The base also serves to neutralize the reactionproduct mixture. The temperture and duration of the reaction are notcritical and may be varied, the temperature over the range from to 75 C.and the duration from 10-15 minutes to 1820 hours. It is most convenientto carry out the reaction at room temperature and at that temperature itis usually complete after 46 hours. Equivalent quantities of thereactants are normally employed although a small excess of either is notharmful. A large excess of base should be avoided.

The compounds of the invention are new chemical compounds that areuseful as chemotherapeutic agents having antifungal and antibacterialactivity. As antifungal agents, they are effective against pathogenicand nonpathogenic yeasts such as Candida albicans and human and animalfilamentous fungal pathogens such as T richophyton mentagro hytes. Theantifungal activity of the compounds of the invention can bedemonstrated and quantitatively determined in a test procedure carriedout as follows.

A test compound is serially diluted in pure N,N-dimethylformamide togive concentrations of 20,000, 4000, 800, 160, and 32 micrograms g) /ml.A further dilution of 1:100 is next made from each of these intoduplicate tubes containing 9.4 ml. of Bacto-Sabouraud Dextrose Broth,resulting in two sets of broth tubes having final concentrations of 200,40, 8, 1.6, and 0.32 ig/ml. of test compound in each set. One set ofbroth tubes is then inoculated with 0.5 ml. of a stock suspension ofCandida albicans, containing from 2.0 10" to 6.0 10' viable units/ml.and the other set with 0.5 ml. of a stock solution of Trichophytonmentagrophytes, containing from 4 10 to 4X10 viable units/ml. Followinginoculation, all of the tubes are incubated for 24 hours at 28 C. Thesetubes are used to determine the so-called static test results, that is,the concentration level at which the test compound inhibits growth ofthe organism. After the 24- hour incubation, two serial dilutions of1:100 into Baoto- Sabouraud Dextrose Broth are made from each of thesetubes into a new set of tubes, which are used to determine the so-calledcidal test results, that is, to determine at which of the originalconcentration levels the test compound eifectively kills all of theorganisms. All of the tubes, both static and cidal, are incubated at 28C. for 5-6 days following inoculation. The static tubes are then readsubjectively for evidence of growth or no growth, and the cidal tubesare read for killed organisms.

The results obtained in the foregoing test method for the compounds ofthe invention are summarized in the following table, where the compoundsare identified by reference to the examples that follow and the activityof each is expressed in terms of the minimum inhibitory concentration(MIC) against the test organisms.

ANTIFUN GAL ACTIVITY MIC, pg./ml., against Trichoph' lon Candidaalbicans mentagrophytes Compound Static Cidal Static Cidal Example:

EXAMPLE 1 To a slurry of 35.1 g. of Z-mercaptothiazole in 1.5 liters ofmethanol is added 16.2 g. of sodium methoxide, and the resulting mixtureis filtered. To the filtrate is added 62.8 g. of2-bromo-5-nitrothiazole, and the reaction mixture is stirred at roomtemperature for 30 minutes. Upon chilling, there is obtained from themixture a solid pre cipitate of -nitr0-2,2'-thiobisthiazole, which isisolated and purified by crystallization from acetonitrile; m.p. 122124C.

EXAMPLE 2 EXAMPLE 3 A mixture consisting of 2.09 g. of 2-bromo 5nitrothiazole, 1.45 g. of 4,5-dimethyl-2-mercaptothiazole, and 50 ml. ofacetone is stirred at room temperature for 4 hours, and the resultingsolid precipitate is isolated. It is 4,5-dimethyl-'-nitro-2,2'-thiobisthiazole; m.p. 109-112 C., following crystallizationfrom methanol.

EXAMPLE 4 A mixture of 0.58 g. of2-mercapto-4,5,6,7-tetrahydrobenzothiazole and 0.18 g. of sodiummethoxide in warm methanol is stirred for 5-10 minutes and filtered. Tothe filtrate is added 0.71 g. of 2-bromo-5-nitrothiazole, and theresulting mixture is stirred at room temperature for 18 hours. The solidprecipitate of 4,5,6,7-tetrahydro-2 where R represents a member of theclass consisting of 2-thiazolyl, 4-methyl-2-thiazolyl,4-ethyl-2-thiazolyl, 4,5- dimethyl-Z-thiazolyl, and 4,5,6,7-tetrahydro 2benzothiazolyl.

2. A compound according to Claim 1 which is S-nitro-2,2-thiobisthiazole.

3. A compound according to Claim 1 which is4-methly-5'-nitro-2,2-thiobisthiaz0le.

4. A compound according to Claim 1 which is 4-ethyl-5-nitro-2,2-thiobisthiazole.

5. A compound according to Claim 1 which is 4,5-dimethyl--nitro-2,2-thiobisthiazole.

6. A compound according to Claim 1 which is 4,5,6,7- tetrahydro-2-[ (5-nitro-2-thiazolyl) thio] benzothiazole.

References Cited Elderfield (ed.): Heterocyclic Compounds, vol. 5, NewYork, John Wiley & Sons, pp. 565-6 (1957).

Todesco et al.: Chem. Abstracts, :48198W (1971).

RICHARD J. GALLAGHER, Primary Examiner US. Cl. X.R.

260-302 H, 302 S, 302 R; 424270

1. 5-NITRO-2,2''-THIOBISTHIAZOLE COMPOUNDS THAT ARE REPRESENTED BY THE FORMULA 